Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4

Zamaneh Mikhak, James P Strassner, Andrew D Luster, Zamaneh Mikhak, James P Strassner, Andrew D Luster

Abstract

T cell trafficking into the lung is critical for lung immunity, but the mechanisms that mediate T cell lung homing are not well understood. Here, we show that lung dendritic cells (DCs) imprint T cell lung homing, as lung DC-activated T cells traffic more efficiently into the lung in response to inhaled antigen and at homeostasis compared with T cells activated by DCs from other tissues. Consequently, lung DC-imprinted T cells protect against influenza more effectively than do gut and skin DC-imprinted T cells. Lung DCs imprint the expression of CCR4 on T cells, and CCR4 contributes to T cell lung imprinting. Lung DC-activated, CCR4-deficient T cells fail to traffic into the lung as efficiently and to protect against influenza as effectively as lung DC-activated, CCR4-sufficient T cells. Thus, lung DCs imprint T cell lung homing and promote lung immunity in part through CCR4.

Figures

Figure 1.
Figure 1.
Lung DC–activated T cells home efficiently into the lung in response to inhaled antigen. DCs isolated from Flt3L-expanded C57BL/6 mice were used to activate Thy1.1+ OTII cells in vitro. DC-activated OTII cells were adoptively transferred into separate Thy1.2+ C57BL/6 recipient mice, followed by three inhaled OVA challenges. (a) BAL from recipients of DC-activated OTII cells were analyzed for Thy1.1+ (y axis) versus Thy1.2+ (x axis) expression in the CD4+ gate. (b) Thy1.1+ OTII cells in the BAL and lung from recipients of DC-activated T cells were enumerated 24 h after the last OVA challenge. n = 8–38 mice per group total from 2–10 independent experiments for a and b. P-values are calculated between recipients of lung DC– versus other DC-activated T cells. (c) Flow cytometry of lung DCs isolated from Flt3L-expanded mice gating on live CD11c+ cells, demonstrating the expression of CD11c (y axis) versus autofluorescence (AF) in the FITC open channel (x axis). Data are representative of three independent experiments. (d) Thy1.1+ OTII cells in the spleen and PPs from recipients of DC-activated T cells were enumerated. n = 2–3 independent experiments. (e) Lung tissue from recipients of lung DC– versus skin DC–activated OTII cells were stained with H&E and scored by histology. n = 9–10 mice per group total from three independent experiments. Bars, 150 µm. (f) DCs isolated from unexpanded C57BL/6 mice were used to activate Thy1.1+ OTII cells in vitro, which were then adoptively transferred into separate Thy1.2+ C57BL/6 recipient mice, followed by three inhaled OVA challenges. Thy1.1+ OTII cells in the BAL and lung from recipients of DC-activated OTII cells were enumerated. n = 9–23 mice per group total from three to six independent experiments. (g) DCs isolated from Flt3L-expanded C57BL/6 mice were used to activate Thy1.2+ OTI cells in vitro. DC-activated OTI cells were adoptively transferred into separate Thy1.1+ C57BL/6 recipient mice, followed by three inhaled OVA challenges. Thy1.2+ OTI cells in the BAL and lung from recipients of DC-activated OTI cells were enumerated. n = 6–15 mice per group total from two to four independent experiments. *, P < 0.05; **, P < 0.005; ***, P < 0.0005; ****, P < 0.00005. Data are presented as mean (±SEM).
Figure 2.
Figure 2.
The homing advantage of lung DC–activated T cells in response to antigen is specific to the lung. DCs isolated from Flt3L-expanded C57BL/6 mice were used to activate OTII cells in vitro. DC-activated T cells were adoptively transferred into separate recipient mice, followed by oral, i.p., or epicutaneous OVA challenges. DC-activated Thy1.1+ OTII cells were transferred into Thy1.2+ C57BL/6 recipients in a–c. DC-activated Thy1.2+ OTII cells were transferred into Thy1.1+ C57BL/6 recipients in d. (a) Thy1.1+ OTII cells in LP, PPs, lung, and spleen from recipients of lung DC– versus MLN DC–activated T cells were enumerated 24 h after one oral OVA challenge. (b) PPs from recipients of lung DC– versus MLN DC–activated T cells after one oral OVA challenge were analyzed for the expression of CD4+ (y axis) and Thy1.1+ (x axis, right) by flow cytometry. (c) Thy1.1+ OTII cells in PPs, lung, and spleen from recipients of lung DC– versus MLN DC–activated T cells were enumerated 24 h after one i.p. OVA challenge. (d) Thy1.2+ OTII cells in the ear skin, lung, and spleen from recipients of lung DC– versus SLN DC–activated T cells were enumerated 24 h after three daily tape strippings and epicutaneous OVA challenges. n = 12 mice per group total from three independent experiments in a and b for PPs, lung, and spleen. n = 6 mice per group total from two independent experiments in a for LP and in c and d. *, P < 0.05. Data are presented as mean (±SEM).
Figure 3.
Figure 3.
Lung-imprinting DCs are migratory DCs. Lung and TLN DCs isolated from Flt3L-expanded C57BL/6 mice 30 min or 24 h after intranasal OVA with or without intranasal CCR7 or CCR4 blocking antibody were used to activate Thy1.1+ OTII cells in vitro. DC-activated T cells were adoptively transferred into separate Thy1.2+ recipient C57BL/6 mice, followed by three inhaled OVA challenges. Thy1.1+ OTII cells in the lung from recipients of lung DC– versus TLN DC–activated T cells were enumerated when DCs were isolated either 30 min or 24 h after intranasal OVA exposure. n = 7–20 mice per group total from two to five independent experiments. *, P < 0.05; ***, P < 0.0005. Data are presented as mean (±SEM).
Figure 4.
Figure 4.
Lung DC–activated T cells home efficiently into the lung at homeostasis. DCs isolated from Flt3L-expanded C57BL/6 mice were used to activate Thy1.1+ OTII cells in vitro. DC-activated T cells were adoptively transferred into separate recipient Thy1.2+ C57BL/6 mice without OVA challenges. (a) Thy1.1+ OTII cells in the BAL and lung from recipients of DC-activated T cells were enumerated 72 h after adoptive transfer. n = 9 mice per group total from three independent experiments. (b and c) DCs were isolated from Flt3L-expanded mice. CFSE-labeled, lung DC–activated T cells and CMTMR-labeled, MLN DC– or SLN DC–activated T cells were mixed 1:1 and adoptively transferred into recipient mice without OVA challenges. (b) HI (y axis) for the lung, spleen, PPs, and SLNs (x axis) was determined 4 h after competitive adoptive transfer of lung DC– and MLN DC–activated T cells (left; n = 9 mice total from three independent experiments) and lung DC– and SLN DC–activated T cells (right; n = 9 mice total from three independent experiments). Gating on 7-AAD−CD4+ cells within the lymphocyte gate, HI was calculated as [CFSE+/CMTMR+]tissue/[CFSE+/CMTMR+]input. P-values are calculated between the HI for any tissue versus the HI for spleen. (c) CFSE+ lung DC–activated T cells (y axis) versus CMTMR+ MLN DC (x axis, top)– or SLN DC–activated T cells (x axis, bottom) were analyzed, demonstrating input cells and gated cells in the lung, spleen, PPs, and SLNs. *, P < 0.05; **, P < 0.005; ***, P < 0.0005; ****, P < 0.00005. Data are presented as mean (±SEM).
Figure 5.
Figure 5.
Expression of trafficking molecules by lung DC–activated T cells. DCs isolated from Flt3L-expanded C57BL/6 mice were used to activate OTII cells in vitro in a–e. (a) Thy1.1+ DC-activated OTII cells were either treated or untreated with PTX and adoptively transferred into Thy1.2+ recipient mice, followed by three inhaled OVA challenges. Thy1.1+ OTII cells were enumerated in the BAL and lung from recipients of PTX-treated or untreated, lung DC–activated T cells. n = 6 mice per group total from two independent experiments. (b–e) DC-activated T cells were analyzed for expression of trafficking molecules on day 5. (b) Percentage (left) and mean fluorescence intensity (MFI; right) of CCR4+ lung DC–, MLN DC–, and SLN DC–activated T cells. n = 8 independent experiments. (c) Flow cytometry of lung DC–, MLN DC–, and SLN DC–activated T cells demonstrating the expression of CD4 (x axis) versus CCR4 (top row), α4β7 (second row), CCR9 (third row), and E-selectin ligand (bottom row; y axis). (d) Percentage of α4β7+ (top), CCR9+ (middle), and E-selectin ligand+ (bottom) lung DC–, MLN DC–, and SLN DC–activated T cells. n = 6–10 separate cultures. (e) Percent expression of chemokine receptors (left) and integrins and selectin ligands (right) by lung DC–, MLN DC–, and SLN DC–activated T cells. n = 4–8 independent experiments. (f) Percent expression of chemokine receptors (left) and integrins and selectin ligands (right) by CD4+ T cells in the lymphocyte gate in lungs isolated from naive C57BL/6 mice. n = 3–10 individual lungs. *, P < 0.05; **, P < 0.005; ***, P < 0.0005; ****, P < 0.00005. Data are presented as mean (±SEM).
Figure 6.
Figure 6.
CCR4 contributes to the lung-homing advantage of lung DC–activated T cells. (a) RNA expression of CCR4 (CCL17 and CCL22), CCR6 (CCL20), and CXCR3 ligands (CXCL9 and CXCL10) in lungs of naive C57BL/6 mice. n = 8 mice. (b) Immunohistochemistry staining with CCL17 antibody (middle and right) or isotype control antibody (left) in lungs of naive mice (left and middle) and mice that received lung DC–activated OTII cells, followed by three daily inhaled OVA challenges (right), demonstrating CCL17 expression by both epithelial (top) and endothelial cells (bottom). Staining with the isotype control antibody in the lungs of mice that received OTII cells and OVA was similar to that of naive mice (not depicted). n = 13 samples from three independent experiments. Bars, 20 µm. (c) Lung HI. DCs isolated from Flt3L-expanded mice were used to activate OTII and CCR4−/− OTII cells. CFSE-labeled, lung DC–activated CCR4−/− OTII cells and CMTMR-labeled, MLN DC– or SLN DC–activated CCR4−/− OTII cells were mixed 1:1 and adoptively transferred into recipient C57BL/6 mice without OVA challenges. CFSE-labeled, lung DC–activated OTII cells and CMTMR-labeled, MLN DC– or SLN DC–activated OTII cells were also mixed 1:1 and adoptively transferred into another set of recipient C57BL/6 mice without OVA challenges. Gating on 7-AAD−CD4+ cells within the lymphocyte gate, HI for the lung at 4 h after cotransfer was calculated as [CFSE+/CMTMR+]lung/[CFSE+/CMTMR+]input. P-values are calculated between the HIs for the lung after the competitive transfer of CCR4−/− OTII cells versus OTII cells. n = 6–13 mice total from two to four independent experiments. (d) Lung DCs isolated from Flt3L-expanded mice were used to activate Thy1.2+ OTII and CCR4−/− OTII cells. Lung DC–activated OTII and CCR4−/− OTII cells were adoptively transferred into separate Thy1.1+ recipient mice, followed by three inhaled OVA challenges. Thy1.2+ OTII cells in the BAL and lung of recipient mice were enumerated 24 h after the last OVA challenge. n = 9 mice per group total from three independent experiments. *, P < 0.05; **, P < 0.005. Data are presented as mean (±SEM).
Figure 7.
Figure 7.
Lung DC–activated T cells protect against influenza. DCs isolated from Flt3L-expanded mice were used to activate Thy1.2+ OTII or CCR4−/− OTII cells in vitro. DC-activated T cells were adoptively transferred into separate Thy1.1+ C57BL/6 recipient mice. 72 h after adoptive transfer, mice were infected intranasally with 105 PFU of a live OVA323–339 expressing PR8-H1N1 influenza virus (H1ova). Lungs were harvested 72 h after infection for analysis. (a, left) Number of Thy1.2+ OTII cells in the lung from recipients of DC-activated T cells infected with H1ova. n = 5–8 mice per group in two independent experiments. P-values are calculated between recipients of lung DC-activated OTII cells versus other groups. (right) Lung flow cytometry from recipients of DC-activated T cells infected with H1ova, demonstrating Thy1.1+ (y axis) versus Thy1.2+ (x axis) cells in the CD4+ gate within the lymphocyte gate. (b) RNA expression of CCL17 and CCL22 in the lungs of mice that were infected with H1ova. n = 6–14 mice per time point in three independent experiments. (c–e) Recipients of either no cells or lung, MLN, or SLN DC–activated OTII cells or lung DC–activated CCR4−/− OTII cells were infected with H1ova as in a. n = 16–42 mice per group total from 4–11 independent experiments for c and d. n = 5–13 mice per group total from four independent experiments for e. (c) Percentage of original weight versus days after infection. (d) Percentage of surviving mice versus days after infection. (e) Viral RNA copies for the polymerase gene of the PR8 influenza virus in the lungs at day 10 after infection. *, P < 0.05; **, P < 0.005; ***, P < 0.0005. Data for a–e are presented as mean (±SEM).

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Source: PubMed

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